tbuckley/cabot-search huggingface dataset:
Benralizumab for eosinophilic granulomatosis with polyangiitis
Authors: Adrien Cottu, Matthieu Groh, Charlene Desaintjean, Sylvain Marchand-Adam, Loïc Guillevin, Xavier Puechal, Stacy Beaumesnil, Estibaliz Lazaro, Maxime Samson, Camille Taille, Cécile-Audrey Durel, Elizabeth Diot, Sarah Nicolas, Laurent Guilleminault, Mikael Ebbo, Pascal Cathebras, Clairelyne Dupin, Halil Yildiz, Nabil Belfeki, Grégory Pugnet, Pierre Chauvin, Stephane Jouneau, Francois Lifermann, Jean-Philippe Martellosio, Vincent Cottin, Benjamin Terrier
Journal: Annals of the Rheumatic Diseases (2023)

Benralizumab is effective in the treatment of eosinophilic asthma and is being investigated for the treatment of other eosinophil-associated diseases. Reports on the use of benralizumab for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) are limited to case reports and small case series.We conducted a multicentre, retrospective study including EGPA patients treated with off-label benralizumab. The primary endpoint was the rate of complete response defined as no disease activity (Birmingham Vasculitis Activity Score=0) and a prednisone dose ≤4 mg/day. Partial response was defined as no disease activity and a prednisone dose ≥4 mg/day.Sixty-eight patients were included, including 31 (46%) who had previously received mepolizumab. The use of benralizumab was warranted by uncontrolled asthma in 54 (81%), persistent ear, nose and throat (ENT) manifestations in 27 (40%) and persistent glucocorticoids (GCs) use in 48 (74%) patients. Median (IQR) follow-up after starting benralizumab was 23 (9-34) months. Thirty-three patients (49%) achieved a complete response, 24 (36%) achieved a partial response and 10 (15%) did not respond. Among the 57 patients who initially responded, 10 (18%) eventually required further line treatments. GCs were discontinued in 23 patients (38%). Prior mepolizumab use was associated with a higher rate of primary failure (26.7% vs 5.4%, p=0.034) and less frequent GCs discontinuation (14.8% vs 55.9%, p=0.001). Vasculitis flares occurred in 7 patients (11%) and were associated with histological evidence of vasculitis and/or antineutrophil cytoplasmic antibodies positivity at benralizumab initiation (p=0.004).Benralizumab appears to be an effective treatment for refractory asthma or ENT manifestations in EGPA and allows GC-sparing. However, its efficacy was lower after prior failure of mepolizumab.
Fluorinated amphiphilic Poly(β-Amino ester) nanoparticle for highly efficient and specific delivery of nucleic acids to the Lung capillary endothelium
Authors: Zicheng Deng, Wen Gao, Fatemeh Kohram, Enhong Li, Tanya V. Kalin, Donglu Shi, Vladimir V. Kalinichenko
Journal: Bioactive Materials (2023)

Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension, viral and bacterial pneumonia, bronchopulmonary dysplasia, and congenital lung diseases such as alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). To correct endothelial dysfunction, there is a critical need for the development of nanoparticle systems that can deliver drugs and nucleic acids to endothelial cells with high efficiency and precision. While several nanoparticle delivery systems targeting endothelial cells have been recently developed, none of them are specific to lung endothelial cells without targeting other organs in the body. In the present study, we successfully solved this problem by developing non-toxic poly(β-amino) ester (PBAE) nanoparticles with specific structure design and fluorinated modification for high efficiency and specific delivery of nucleic acids to the pulmonary endothelial cells. After intravenous administration, the PBAE nanoparticles were capable of delivering non-integrating DNA plasmids to lung microvascular endothelial cells but not to other lung cell types. IVIS whole body imaging and flow cytometry demonstrated that DNA plasmid were functional in the lung endothelial cells but not in endothelial cells of other organs. Fluorination of PBAE was required for lung endothelial cell-specific targeting. Hematologic analysis and liver and kidney metabolic panels demonstrated the lack of toxicity in experimental mice. Thus, fluorinated PBAE nanoparticles can be an ideal vehicle for gene therapy targeting lung microvascular endothelium in pulmonary vascular disorders.
Empowering women facing gender-based violence amid COVID-19 through media campaigns
Authors: Fotini Christia, Horacio Larreguy, Elizabeth Parker-Magyar, Manuel Quintero
Journal: Nature Human Behaviour (2023)

COVID-19 heightened women's exposure to gender-based and intimate partner violence, especially in low-income and middle-income countries. We tested whether edutainment interventions shown to successfully combat gender-based and intimate partner violence when delivered in person can be effectively delivered using social (WhatsApp and Facebook) and traditional (TV) media. To do so, we randomized the mode of implementation of an intervention conducted by an Egyptian women's rights organization seeking to support women amid COVID-19 social distancing. We found WhatsApp to be more effective in delivering the intervention than Facebook but no credible evidence of differences across outcomes between social media and TV dissemination. Our findings show little credible evidence that these campaigns affected women's attitudes towards gender or marital equality or on the justifiability of violence. However, the campaign did increase women's knowledge, hypothetical use and reported use of available resources.
Genome-wide analysis of a model-derived binge eating disorder phenotype identifies risk loci and implicates iron metabolism
Authors: David Burstein, Trevor C Griffen, Karen Therrien, Jaroslav Bendl, Sanan Venkatesh, Pengfei Dong, Amirhossein Modabbernia, Biao Zeng, Deepika Mathur, Gabriel Hoffman, Robyn Sysko, Tom Hildebrandt, Georgios Voloudakis, Panos Roussos
Journal: Nature Genetics (2023)
PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework
Authors: Alexander J. M. Dingemans, Max Hinne, Kim M. G. Truijen, Lia Goltstein, Jeroen van Reeuwijk, Nicole de Leeuw, Janneke Schuurs-Hoeijmakers, Rolph Pfundt, Illja J. Diets, Joery den Hoed, Elke de Boer, Jet Coenen-van der Spek, Sandra Jansen, Bregje W. van Bon, Noraly Jonis, Charlotte W. Ockeloen, Anneke T. Vulto-van Silfhout, Tjitske Kleefstra, David A. Koolen, Philippe M. Campeau, Elizabeth E. Palmer, Hilde Van Esch, Gholson J. Lyon, Fowzan S. Alkuraya, Anita Rauch, Ronit Marom, Diana Baralle, Pleuntje J. van der Sluijs, Gijs W. E. Santen, R. Frank Kooy, Marcel A. J. van Gerven, Lisenka E. L. M. Vissers, Bert B. A. de Vries
Journal: Nature Genetics (2023)
Computational optimization of antibody humanness and stability by systematic energy-based ranking
Authors: Ariel Tennenhouse, Lev Khmelnitsky, Razi Khalaila, Noa Yeshaya, Ashish Noronha, Moshit Lindzen, Emily K Makowski, Ira Zaretsky, Yael Fridmann Sirkis, Yael Galon-Wolfenson, Peter M Tessier, Jakub Abramson, Yosef Yarden, Deborah Fass, Sarel J Fleishman
Journal: Nature Biomedical Engineering (2023)
Endoscopically guided interventional photodynamic therapy for orthotopic pancreatic ductal adenocarcinoma based on NIR-II fluorescent nanoparticles
Authors: Kang Chen, Baoli Yin, Quanneng Luo, Yi Liu, Yi Wang, Yan Liao, Yuhang Li, Xu Chen, Bo Sun, Ning Zhou, Hongwen Liu, Chuang Peng, Sulai Liu, Wei Cheng, Guosheng Song
Journal: Theranostics (2023)

Rationale: Pancreatic cancer, comprising mostly pancreatic ductal adenocarcinoma (PDAC), is a highly malignant disease, typically known as a hypoxic tumor microenvironment. The application of PDT in pancreatic cancer in clinic is still hampered by several shortcomings, including the (i) deep location of pancreatic cancer, (ii) tissue damage induced by optical fibers, (iii) hypoxic microenvironment, (iv) short excitation wavelengths of traditional photosensitizers, and (v) poor delivery efficiency of photosensitizers. Methods: We designed an organic nanoparticle as photosensitizer for near-infrared II (NIR-II) fluorescent (FL) imaging that exerts a type I PDT effect on deep orthotopic pancreatic tumors under excitation by a NIR (808 nm) laser. Results: This novel photosensitizer exhibits enhanced accumulation in orthotopic pancreatic cancer in mice and could be used to effectively detect pancreatic cancer and guide subsequent laser irradiation for accurate PDT of deep pancreatic cancer. In addition, we built an endoscopic platform monitored by NIR-II FL imaging to achieve minimally invasive endoscopically guided interventional photodynamic therapy (EG-iPDT) with efficient inhibition of orthotopic pancreatic cancer, which prolonged overall survival up to 78 days compared to PBS + EG-iPDT group (*p < 0.05) in a mouse model. Conclusions: Minimally invasive EG-iPDT has promise as an intraoperative treatment for early-stage or unresectable or metastatic pancreatic cancer.
Regulatory mechanisms and therapeutic implications of insulin-like growth factor 2 mRNA-binding proteins, the emerging crucial m<sup>6</sup>A regulators of tumors
Authors: Heng Zhou, Qiang Sun, Mingliang Feng, Ziming Gao, Shiheng Jia, Lanxin Cao, Xue Yu, Shan Gao, Huizhe Wu, Kai Li
Journal: Theranostics (2023)

Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) serve essential biological functions as post-transcriptional performers, participating in the acquisition or maintenance of tumor hallmarks due to their distinct protein structures.Emerging evidence indicates that IGF2BPs belong to the class III type of RNA N 6 -methyladenosine (m 6 A) modification readers, controlling RNA stability, storage, localization, metabolism, and translation in multiple vital bioprocesses, particularly tumorigenesis and tumor progression.Here, we discuss the underlying regulatory mechanisms and pathological functions of IGF2BPs which act as m 6 A readers in the context of tumor pathogenesis and multidrug resistance.Furthermore, we highlight the potential of IGF2BPs as drug targets in clinical tumor treatment.Hence, precise and novel tumor therapeutic approaches could be uncovered by targeting epigenetic heterogeneity.
Erythroid-transdifferentiated myeloid cells promote portal vein tumor thrombus in hepatocellular carcinoma
Authors: Wei-Hang Zhu, Jie Chen, Run-Kai Huang, Yuan Zhang, Ze-Xuan Huang, Xiu-Qing Pang, Bo Hu, Yang Yang, Xing Li
Journal: Theranostics (2023)

Rationale: Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor thrombus (PVTT) in HCC remains unclear. As a consequence of myeloid cell developmental arrest, CD71+ erythroid progenitor cells (EPCs) and myeloid-derived suppressor cells play important roles in HCC; however, their roles in PVTT remain unclear. Methods: The role of CD71+ EPCs in the HCC tumor microenvironment (TME) was evaluated via morphological, RNA-sequencing, enzyme-linked immunosorbent assay, and flow cytometric analyses. Co-culture techniques were employed to assess the CD45+ EPCs and their vascular compromising effect. Additionally, the PVTT-promoting function of CD45+ EPCs was explored in vivo in a murine model. Results: The CD45+EPCs in HCC tissues exhibited increased myeloid cell features, including morphology, surface markers, transforming growth factor (TGF)-β generation, and gene expression, compared with those in circulation. Hence, a large proportion of CD45+EPCs, particularly those in TMEs, comprise erythroid-transdifferentiated myeloid cells (EDMCs). Additionally, the expression of C-C chemokine receptor type 2 (CCR2) mRNA was upregulated in CD45+EPCs within the TME. Tumor macrophages from HCC tissues induced substantial migration of CD45+EPCs in a dose-dependent manner. Meanwhile, results from immunofluorescence analyses revealed that these two cell types are positively associated in the TME and circulation. That is, EDMCs are chemoattracted by HCC macrophages mainly via CCR2 from CD45+ EPCs in the circulation. Additionally, the expressions of FX, FVII, FGB, C4b, CFB, and CFH were elevated in CD45+EPCs within the TME compared with those in the spleen. The CD45+EPCs from the HCC TME promoted vessel endothelial cell migration and compromised tube formation through TGF-β and FGB, respectively. Additionally, CD45+EPCs from the TME induced HCC cell migration. HCC macrophage-induced CD45+EPCs to exhibit higher levels of FX, FVII, FGB, and TGF-β. Meanwhile, upregulation of CCAAT/enhancer binding protein beta expression induced FGB and TGF-β generation in CD45+EPCs in the TME. WTAP, a major RNA m6A writer, stabilized FX and FVII mRNA and enhanced their nuclear export in CD45+EPCs from the TME. CD45+EPCs from the TME were positively associated with PVTT and poor prognosis. Splenectomy reduced the level of CD45+EPCs in the circulation and TME, as well as the incidence of microvascular invasion. The incidence of microvascular invasion increased following the transfer of HCC tissue CD45+EPCs to splenectomized HCC-bearing mice. Conclusions: The CD45+EPCs enriched in the HCC microenvironment are EDMCs, which are induced by HCC macrophages to migrate from the circulation to the TME. Subsequently, EDMCs promote PVTT by compromising the blood vessel endothelium, aggravating coagulation, and promoting HCC cell migration.
Secretome of senescent hepatic stellate cells favors malignant transformation from nonalcoholic steatohepatitis-fibrotic progression to hepatocellular carcinoma
Authors: Yuan Zhou, Li Zhang, Yue Ma, Li Xie, Yong-yu Yang, Cheng Jin, Hui Chen, Ying Zhou, Guang-qi Song, Jia Ding, Jian Wu
Journal: Theranostics (2023)

Background: Hepatic fibrosis is a premalignant lesion, and how injured hepatocytes transform into malignancy in a fibrotic microenvironment is poorly understood. Senescence is one of major fates of activated hepatic stellate cells (HSCs). Paucity of literature is available regarding the influence of senescent HSCs on behavior of steatotic hepatocytes. Methods: Senescent HSCs were identified in a murine model of nonalcoholic steatohepatitis (NASH)-fibrosis-hepatocellular carcinoma (HCC) and human NASH-HCC specimens. Secretome of senescent HSCs was analyzed by label-free mass-spectrum (NanoRPLC-MS/MS) and verified quantitatively. Results: Senescent HSCs were increased along with the progression from nonalcoholic fatty liver (NAFL), NASH to NASH-fibrosis, and reached a peak at the stage of advanced fibrosis and then decreased when hepatocellular dysplasia or HCC was developed. Critical components affecting proliferation, epithelial-mesenchymal transition (EMT) or migration were identified from secretome of senescent HSCs, and may activate morphogenic hedgehog or oncogenic Wnt signaling pathways to accelerate malignant transformation of steatotic or dysplastic hepatocytes. Primary hepatocytes stimulated with conditioned medium from senescent HSCs, in co-culture or co-cultured in 3D spheroids with senescent HSCs exhibited an enhanced proliferating or EMT profile. Conclusion: Senescent HSCs secreted a characterized protein profile favoring malignant transformation of steatotic or dysplastic hepatocytes through activating morphogenic hedgehog or oncogenic Wnt signaling pathways in the progression from NASH to malignancy.
Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression
Authors: Chengmin Liu, Ke Jiang, Yanyan Ding, Aihua Yang, Renwei Cai, Panzhu Bai, Minggang Xiong, Changying Fu, Meiling Quan, Zailin Xiong, Yi Deng, Ruijun Tian, Chuanyue Wu, Ying Sun
Journal: Theranostics (2023)

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor, with extremely low survival rates.Identifying key signaling pathways driving PDAC progression is crucial for the development of therapies to improve patient response rates.Kindlin-2, a multi-functional protein, is involved in numerous biological processes including cell proliferation, apoptosis and migration.However, little is known about the functions of Kindlin-2 in pancreatic cancer progression in vivo.Methods: In this study, we employ an in vivo PDAC mouse model to directly investigate the role of Kindlin-2 in PDAC progression.Then, we utilized RNA-sequencing, the molecular and cellular assays to determine the molecular mechanisms by which Kindlin-2 promotes PDAC progression.Results: We show that loss of Kindlin-2 markedly inhibits Kras G12D -driven pancreatic cancer progression in vivo as well as in vitro.Furthermore, we provide new mechanistic insight into how Kindlin-2 functions in this process, A fraction of Kindlin-2 was localized to the endoplasmic reticulum and associated with the RNA helicase DDX3X, a key regulator of mRNA translation.Loss of Kindlin-2 blocked DDX3X from binding to the 5'-untranslated region of c-Myc and inhibited DDX3X-mediated c-Myc translation, leading to reduced c-Myc-mediated glucose metabolism and tumor growth.Importantly, restoration of the expression of either the full-length Kindlin-2 or c-Myc, but not that of a DDX3X-binding-defective mutant of Kindlin-2, in Kindlin-2 deficient PDAC cells, reversed the inhibition of glycolysis and pancreatic cancer progression induced by the loss of Kindlin-2.Conclusion: Our studies reveal a novel Kindlin-2-DDX3X-c-Myc signaling axis in PDAC progression and suggest that inhibition of this signaling axis may provide a promising therapeutic approach to alleviate PDAC progression.
Prognostic value of circumferential radial margin involvement in esophagectomy for esophageal cancer: a case series
Authors: Thomas Boerner, Rebecca Carr, Meier Hsu, Kay See Tan, Carlie Sigel, Laura Tang, Caitlin Harrington, Geoffrey Y. Ku, David H. Ilson, Yelena Y. Janjigian, Abraham J. Wu, Smita Sihag, Manjit S. Bains, Matthew J. Bott, James M. Isbell, Bernard J. Park, David R. Jones, Daniela Molena
Journal: International Journal of Surgery (2023)

Background: Residual tumor at the proximal or distal margin after esophagectomy is associated with worse survival outcomes; however, the significance of the circumferential resection margin (CRM) remains controversial. In this study, we sought to evaluate the prognostic significance of the CRM in patients with esophageal cancer undergoing resection. Materials and Methods: We identified patients who underwent esophagectomy for pathologic T3 esophageal cancer from 2000 to 2019. Patients were divided into three groups: CRM– (residual tumor &gt;1 mm from the CRM), CRM-close (residual tumor &gt;0-1 mm from the CRM), and CRM+ (residual tumor at the surgical CRM). CRM was also categorized and analyzed per Royal College of Pathologists (RCP) and College of American Pathologists (CAP) classifications. Results: Of the 519 patients included, 351 (68%) had CRM–, 132 (25%) had CRM-close, and 36 (7%) had CRM+. CRM+ was associated with shorter disease-free survival (DFS; CRM+ vs. CRM–: hazard ratio [HR], 1.53 [95% CI, 1.03-2.28]; P =0.034) and overall survival (OS; CRM+ vs. CRM–: HR, 1.97 [95% CI, 1.32-2.95]; P &lt;0.001). Survival was not significantly different between CRM-close and CRM–. After adjustment for potential confounders, CAP+ was associated with poor oncologic outcomes (CAP+ vs. CAP–: DFS: HR, 1.47 [95% CI, 1.00-2.17]; P =0.050; OS: HR, 1.93 [95% CI, 1.30-2.86]; P =0.001); RCP+ was not (RCP+ vs. RCP-: DFS: HR, 1.21 [95% CI, 0.97-1.52]; P =0.10; OS: HR, 1.21 [95% CI, 0.96-1.54]; P =0.11). Conclusion: CRM status has critical prognostic significance for patients undergoing esophagectomy: CRM+ was associated with worse outcomes, and outcomes between CRM-close and CRM– were similar.
Severe food allergy reactions are associated with α-tryptase
Authors: Abigail Lang, Stephanie Kubala, Megan C. Grieco, Allyson Mateja, Jacqueline Pongracic, Yihui Liu, Pamela A. Frischmeyer-Guerrerio, Rajesh Kumar, Jonathan J. Lyons
Journal: Journal of Allergy and Clinical Immunology (2023)
CD90-targeted lentiviral vectors for HSC gene therapy
Authors: Kurt Berckmueller, Justin Thomas, Eman A. Taha, Seunga Choo, Ravishankar Madhu, Greta Kanestrom, Peter B. Rupert, Roland Strong, Hans-Peter Kiem, Stefan Radtke
Journal: Molecular Therapy (2023)

Hematopoietic stem cell (HSC) gene therapy is currently performed on CD34
3D organization of regulatory elements for transcriptional regulation in Arabidopsis
Authors: Li Deng, Qiangwei Zhou, Jie Zhou, Qing Zhang, Zhibo Jia, Guangfeng Zhu, Sheng Cheng, Lulu Cheng, Caijun Yin, Chao Yang, Jinxiong Shen, Junwei Nie, Jian-Kang Zhu, Guoliang Li, Lun Zhao
Journal: Genome biology (2023)

Although spatial organization of compartments and topologically associating domains at large scale is relatively well studied, the spatial organization of regulatory elements at fine scale is poorly understood in plants.
Front Cover Image, Volume 43, Issue 5
Authors: Jesus Shrestha, Keshav Raj Paudel, Hojjatollah Nazari, Vivek Dharwal, Sajad Razavi Bazaz, Matt D. Johansen, Kamal Dua, Philip M. Hansbro, Majid Ebrahimi Warkiani
Journal: Medicinal Research Reviews (2023)

The cover image is based on the Review Article Advanced models for respiratory disease and drug studies by Jesus Shrestha et al., https://doi.org/10.1002/med.21956.
Abstract 3603: Extreme Lipoprotein(a) Levels Predict a 3–4 Fold Increase in Risk of Myocardial Infarction in the General Population
Authors: Pia R Kamstrup, Marianne Benn, Anne Tybjćrg Hansen, Børge G Nordestgaard
Journal: Circulation (2007)

Background: Elevated lipoprotein(a) levels associate with increased risk of myocardial infarction in some, but not all studies. Limitations of previous studies include lack of risk estimates for extreme lipoprotein(a) levels, measurements in long-term frozen samples and no correction for regression dilution bias. We tested the hypothesis that extreme lipoprotein(a) levels predict myocardial infarction in the general population, measuring levels shortly after sampling and correcting for regression dilution bias. Methods and Results: We examined 9330 men and women from the Danish general population, The Copenhagen City Heart Study. During 10 years follow-up, 498 participants developed myocardial infarction. In women, multifactorially adjusted hazard ratios for myocardial infarction for elevated lipoprotein(a) levels were 1.1(95% confidence interval 0.6 –1.9) for 5–29 mg/dL, 1.7(1.0 –3.1) for 30 – 84 mg/dL, 2.6(1.2–5.9) for 85–119 mg/dL (&gt;90 th percentile), and 3.6(1.7–7.7) for ≥120 mg/dL (&gt;95 th percentile) versus levels &lt;5 mg/dL (figure , p-values are test for trend of hazard ratios). Equivalent values in men were 1.5(0.9 –2.3), 1.6(1.0 –2.6), 2.6(1.2–5.5), and 3.7(1.7– 8.0). Conclusions: We observed a stepwise increase in risk of myocardial infarction with increasing levels of lipoprotein(a) in both genders, with no evidence of a threshold effect. Extreme lipoprotein(a) levels predict a 3– 4 fold increase in risk of myocardial infarction in the general population. Figure. Risk of myocardial infarction by levels of lipoprotein(a)